Treatment for Primary, Secondary, and Tertiary Syphilis
Benzathine penicillin G is the first-line treatment for all stages of syphilis, with dosage varying by stage: 2.4 million units IM as a single dose for primary and secondary syphilis, and 7.2 million units total (administered as three weekly doses of 2.4 million units) for tertiary syphilis. 1, 2
Primary and Secondary Syphilis
First-Line Treatment
- Benzathine penicillin G 2.4 million units IM in a single dose 3, 2
- For children with acquired primary or secondary syphilis: Benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units in a single dose 3
Alternative Treatments for Penicillin-Allergic Patients
- Doxycycline 100 mg orally twice daily for 14 days 2, 4
- Tetracycline 500 mg orally 4 times a day for 14 days 3
Tertiary Syphilis
First-Line Treatment
- Benzathine penicillin G 7.2 million units total, administered as 3 doses of 2.4 million units IM each at 1-week intervals 2
- For neurosyphilis (which can occur at any stage): Aqueous crystalline penicillin G 18-24 million units per day, administered as 3-4 million units IV every 4 hours or continuous infusion, for 10-14 days 1, 5
Alternative Treatments for Penicillin-Allergic Patients
- For tertiary syphilis without neurosyphilis: Doxycycline 100 mg orally twice daily for 28 days 2, 4
- For neurosyphilis: Penicillin remains the only proven effective treatment; penicillin desensitization is required for allergic patients 1, 6
Special Considerations
HIV Co-infection
- Treatment regimens are the same as for non-HIV-infected patients 2
- More frequent follow-up is recommended (every 3 months instead of 6 months) 1
- CSF examination should be performed for HIV-infected persons with late-latent syphilis or syphilis of unknown duration 1
Pregnancy
- Only penicillin G is proven effective for preventing maternal transmission 2
- Pregnant women with penicillin allergy should undergo desensitization and be treated with penicillin 2
Follow-Up and Monitoring
- Quantitative nontreponemal test titers should be used to monitor treatment response 1
- A fourfold change in titer is considered clinically significant 1
- For primary and secondary syphilis: Clinical and serologic evaluation at 3 and 6 months after treatment 3
- For tertiary syphilis: Clinical and serologic evaluation at 6,12, and 24 months after treatment 1
Treatment Failure
- Treatment failure is defined as failure of nontreponemal test titers to decline 4-fold within 6 months after therapy for primary or secondary syphilis 2
- Re-treatment with weekly injections of benzathine penicillin G 2.4 million units IM for 3 weeks is recommended if treatment failure occurs 2
- CSF examination should be performed if treatment failure is suspected 3
Common Pitfalls and Caveats
- The Jarisch-Herxheimer reaction (fever, chills, headache) may occur within the first 24 hours after any therapy for syphilis; patients should be advised of this possible adverse reaction 3
- Sequential serologic tests should use the same testing method, preferably by the same laboratory 1
- Some patients may remain serofast (persistent low-level positive titers) despite adequate treatment, which does not necessarily indicate treatment failure 1
- Recent research suggests that a single dose of benzathine penicillin G is noninferior to three doses for early syphilis, even in HIV-infected patients 7, but guidelines still recommend stage-specific treatment as outlined above 2